Development and Strategy for In Vitro Companion Diagnostic Devices

Companion diagnostics are crucial for the safety and efficacy of their concomitant drugs and can accelerate the process of personalized drug development. In this article, we introduce the the history, development strategies, and global regulations of in vitro companion diagnostic reagents, development strategies, and global regulations and policies for the reference of the in vitro diagnostic devices industry.

Introduction of Companion Diagnostics

Companion Diagnostics (CDx) is a sub-segment of in vitro diagnostics, a class of in vitro diagnostic devices that can provide important information about the safety and efficacy of a specific drug application.

Companion diagnostics are used in conjunction with therapeutic agents, including similar therapeutic agents, as specified in the labeling instructions for the diagnostic device and the corresponding drug.

On August 6, 2014, the U.S. Food and Drug Administration (FDA) released the official final version of the In Vitro Companion Diagnostic Devices Guidance for Industry and Food and Drug Administration Staff, which explicitly introduced the concept of companion diagnostics for the first time.

In 1998, the FDA approved the first companion diagnostic product, Herceptin-HER2. To date, the FDA has approved a total of 57 companion diagnostic kits. Tumor-related indications account for 93%. Tumors are caused by gene mutations, which demonstrates the value of companion diagnosis. Formalin-fixed and paraffin-embedded (FFPE) tissue samples accounted for 69% of the total, and blood samples accounted for a gradually increasing proportion.

FDA-approved companion diagnostics are primarily based on methodologies including but not limited to:

• Immunohistochemistry (IHC)
• Fluorescence In Situ Hybridization (FISH)
• Chromogenic In Situ Hybridization (CISH)
• Polymerase Chain Reaction (PCR)
• Next-Generation Sequencing (NGS)

Significance of Companion Diagnostics

Companion diagnostic products are critical for the safe and effective use of the therapeutic product in question in the following ways:

• Identifying patients most likely to benefit from a particular therapeutic product
• Identifying patients who may be at increased risk of serious side effects from the use of a particular therapeutic product
• Monitoring patient response to the therapeutic product in order to adjust treatment options (e.g., timing, dosage, discontinuation) to improve safety or efficacy
• Identify groups of patients who have been proven by research to be safe and effective with a particular drug, while there is insufficient information about the safety and effectiveness of the therapeutic agent in other groups

Developmental History

Early exploratory phase

1998: HercepTest

The first approved companion diagnostic, developed by Dako (Agilent Technologies), detects and analyzes overexpression of the HER2 gene as an aid in determining whether a breast cancer patient is a candidate for treatment with Herceptin (Trastuzumab).

2004: EGFR Assay

The FDA approved Roche's Cobas EGFR companion diagnostic reagent for determining whether non-small cell lung cancer patients are candidates for Gefitinib or Erlotinib therapy.

Emergence of precision medicine

2010: BRAF V600E Assay

The FDA approved Roche's Cobas BRAF V600E companion diagnostic reagent to determine the suitability of the BRAF inhibitor Zelboraf (Vemurafenib) for patients with melanoma.

2011: KRAS Mutation Test

The KRAS gene mutation test is used to determine response to Erbitux (Cetuximab) and Vectibix (Panitumumab) in patients with colorectal cancer.

2012: ALK Fusion Gene Test

The FDA approved the Vysis ALK Break Apart FISH companion diagnostic reagent for use in determining the suitability of Crizotinib (Xalkori) therapy for patients with non-small cell lung cancer.

Multi-gene panel and NGS testing phase

2013: FoundationOne CDx

Foundation Medicine launches the FoundationOne multigene testing panel for precision cancer treatment.

2017: FDA approves the first NGS gene panel

FoundationOne CDx is approved by the FDA as the first NGS gene testing panel for companion diagnostics in cancer.

2018: MSK-IMPACT

MSK-IMPACT companion diagnostic reagent developed at MSK was approved by the FDA for use in a multigene test targeting 344 genes.

Global Regulatory Standards and Guidance

United States (FDA)

The FDA is the drug regulatory agency with the earliest start, the most rapid development, the most thorough regulatory documents, and the clearest path to approval in the global companion diagnostics market, so the U.S. regulatory experience is an important reference value.

Europe (EMA)‍

China (NMPA)‍

Development Methods and Strategies

There are three main development methods for companion diagnostics: co-development, bridging, and follow-on.

Co-development

FDA encourages companion diagnostic reagent companies to work closely with drug discovery and development companies to achieve co-approval of companion diagnostic reagents and their companion drugs more economically through co-development.

Co-development means that the development process of companion diagnostic reagents and their companion drugs is completely synchronized with the data from clinical trials, proving each other, which is also the strongest way to develop companion diagnostic clinical data.

Effective co-development of a companion diagnostic reagent with a therapeutic drug typically requires coordination of the development programs for both products, including interaction with all relevant FDA review authorities.

Click here for more detailed guidelines on co-development.

Features

• Participation in drug clinical trials
• Approved concurrently with a companion drug
• Optimal and cost-effective approach encouraged by the FDA

Bridging

If the companion diagnostic reagent being applied for is not the same as the Clinical Trial Assay (CTA) used for the major efficacy trial, the FDA requires the use of a bridging study.

The original clinical trial samples are analyzed to demonstrate that the two methods have very similar performance characteristics.

General Process for Bridging Development Strategies:

Retest CTA-positive and CTA-negative samples with declared companion diagnostic products

Assess the concordance of companion diagnostics with CTA

Bridging clinical data from CTA to companion diagnostic products

Features

• Does not participate in drug clinical trials
• Approved concurrently with a companion drug

Follow-on

If the companion diagnostic company does not have a drug company partner or the samples used in the initial clinical trial are not available, a follow-on approach can be used to demonstrate analytical performance. Follow-on development requires a comparative study of the declared companion diagnostic reagent with a marketed companion diagnostic reagent.

Features

• Does not participate in drug clinical trials
• Not approved at the same time as the companion drug

Proregulations' international service team has extensive experience in domestic and international regulatory and approval matters, as well as a wide range of clinical research resources. Contact us to learn how we can assist our clients with product development and global registration of companion diagnostic reagents.